Brain White Matter Research Articles

Uncovering the hidden effects of repetitive subconcussive head impact exposure: A mega-analytic approach characterizing seasonal brain microstructural changes in contact and collision sports athletes.

Repetitive subconcussive head impacts (RSHI) are believed to induce sub-clinical brain injuries, potentially resulting in cumulative, long-term brain alterations. This study explores patterns of longitudinal brain white matter changes across sports with RSHI-exposure. A systematic literature search identified 22 datasets with longitudinal diffusion magnetic resonance imaging data. Four datasets were centrally pooled to perform uniform quality control and data preprocessing. A total of 131 non-concussed active athletes (American football, rugby, ice hockey; mean age: 20.06 ± 2.06 years) with baseline and post-season data were included. Nonparametric permutation inference (one-sample t tests, one-sided) was applied to analyze the difference maps of multiple diffusion parameters. The analyses revealed widespread lateralized patterns of sports-season-related increases and decreases in mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD) across spatially distinct white matter regions. Increases were shown across one MD-cluster (3195 voxels; mean change: 2.34%), one AD-cluster (5740 voxels; mean change: 1.75%), and three RD-clusters (817 total voxels; mean change: 3.11 to 4.70%). Decreases were shown across two MD-clusters (1637 total voxels; mean change: -1.43 to -1.48%), two RD-clusters (1240 total voxels; mean change: -1.92 to -1.93%), and one AD-cluster (724 voxels; mean change: -1.28%). The resulting pattern implies the presence of strain-induced injuries in central and brainstem regions, with comparatively milder physical exercise-induced effects across frontal and superior regions of the left hemisphere, which need further investigation. This article highlights key considerations that need to be addressed in future work to enhance our understanding of the nature of observed white matter changes, improve the comparability of findings across studies, and promote data pooling initiatives to allow more detailed investigations (e.g., exploring sex- and sport-specific effects).

Association of early life exposure to cold and heat with brain white matter microstructure at age 9-12 years

Association of early life exposure to cold and heat with brain white matter microstructure at age 9-12 years

Alzheimer's disease genetic risk and changes in brain atrophy and white matter hyperintensities in cognitively unimpaired adults.

Reduced brain volumes and more prominent white matter hyperintensities on MRI scans are commonly observed among older adults without cognitive impairment. However, it remains unclear whether rates of change in these measures among cognitively normal adults differ as a function of genetic risk for late-onset Alzheimer's disease, including APOE-ɛ4, APOE-ɛ2 and Alzheimer's disease polygenic risk scores (AD-PRS), and whether these relationships are influenced by other variables. This longitudinal study examined the trajectories of regional brain volumes and white matter hyperintensities in relationship to APOE genotypes (N = 1541) and AD-PRS (N = 1093) in a harmonized dataset of middle-aged and older individuals with normal cognition at baseline (mean baseline age = 66 years, SD = 9.6) and an average of 5.3 years of MRI follow-up (max = 24 years). Atrophy on volumetric MRI scans was quantified in three ways: (i) a composite score of regions vulnerable to Alzheimer's disease (SPARE-AD); (ii) hippocampal volume; and (iii) a composite score of regions indexing advanced non-Alzheimer's disease-related brain aging (SPARE-BA). Global white matter hyperintensity volumes were derived from fluid attenuated inversion recovery (FLAIR) MRI. Using linear mixed effects models, there was an APOE-ɛ4 gene-dose effect on atrophy in the SPARE-AD composite and hippocampus, with greatest atrophy among ɛ4/ɛ4 carriers, followed by ɛ4 heterozygouts, and lowest among ɛ3 homozygouts and ɛ2/ɛ2 and ɛ2/ɛ3 carriers, who did not differ from one another. The negative associations of APOE-ɛ4 with atrophy were reduced among those with higher education (P < 0.04) and younger baseline ages (P < 0.03). Higher AD-PRS were also associated with greater atrophy in SPARE-AD (P = 0.035) and the hippocampus (P = 0.014), independent of APOE-ɛ4 status. APOE-ɛ2 status (ɛ2/ɛ2 and ɛ2/ɛ3 combined) was not related to baseline levels or atrophy in SPARE-AD, SPARE-BA or the hippocampus, but was related to greater increases in white matter hyperintensities (P = 0.014). Additionally, there was an APOE-ɛ4 × AD-PRS interaction in relation to white matter hyperintensities (P = 0.038), with greater increases in white matter hyperintensities among APOE-ɛ4 carriers with higher AD-PRS. APOE and AD-PRS associations with MRI measures did not differ by sex. These results suggest that APOE-ɛ4 and AD-PRS independently and additively influence longitudinal declines in brain volumes sensitive to Alzheimer's disease and synergistically increase white matter hyperintensity accumulation among cognitively normal individuals. Conversely, APOE-ɛ2 primarily influences white matter hyperintensity accumulation, not brain atrophy. Results are consistent with the view that genetic factors for Alzheimer's disease influence atrophy in a regionally specific manner, likely reflecting preclinical neurodegeneration, and that Alzheimer's disease risk genes contribute to white matter hyperintensity formation.

Methodological considerations on diffusion MRI tractography in infants aged 0-2 years: a scoping review.

Diffusion MRI (dMRI) enables studying the complex architectural organization of the brain's white matter (WM) through virtual reconstruction of WM fiber tracts (tractography). Despite the anticipated clinical importance of applying tractography to study structural connectivity and tract development during the critical period of rapid infant brain maturation, detailed descriptions on how to approach tractography in young infants are limited. Over the past two decades, tractography from infant dMRI has mainly been applied in research settings and focused on diffusion tensor imaging (DTI). Only few studies used techniques superior to DTI in terms of disentangling information on the brain's organizational complexity, including crossing fibers. While more advanced techniques may enhance our understanding of the intricate processes of normal and abnormal brain development and extensive knowledge has been gained from application on adult scans, their applicability in infants has remained underexplored. This may partially be due to the higher technical requirements versus the need to limit scan time in young infants. We review various previously described methodological practices for tractography in the infant brain (0-2 years-of-age) and provide recommendations to optimize advanced tractography approaches to enable more accurate reconstructions of the brain WM's complexity. IMPACT: Diffusion tensor imaging is the technique most frequently used for fiber tracking in the developing infant brain but is limited in capability to disentangle the complex white matter organization. Advanced tractography techniques allow for reconstruction of crossing fiber bundles to better reflect the brain's complex organization. Yet, they pose practical and technical challenges in the fast developing young infant's brain. Methods on how to approach advanced tractography in the young infant's brain have hardly been described. Based on a literature review, recommendations are provided to optimize tractography for the developing infant brain, aiming to advance early diagnosis and neuroprotective strategies.

Optimization and validation of low-field MP2RAGE T1 mapping on 0.35T MR-Linac: Toward adaptive dose painting with hypoxia biomarkers.

Stereotactic MR-guided Adaptive Radiation Therapy (SMART) dose painting for hypoxia has potential to improve treatment outcomes, but clinical implementation on low-field MR-Linac faces substantial challenges due to dramatically lower signal-to-noise ratio (SNR) characteristics. While quantitative MRI and T1 mapping of hypoxia biomarkers show promise, T1-to-noise ratio (T1NR) optimization at low fields is paramount, particularly for the clinical implementation of oxygen-enhanced (OE)-MRI. The 3D Magnetization Prepared (2) Rapid Gradient Echo (MP2RAGE) sequence stands out for its ability to acquire homogeneous T1-weighted contrast images with simultaneous T1 mapping. To optimize MP2RAGE for low-field T1 mapping; conduct experimental validation in a ground-truth phantom; establish feasibility and reproducibility of low-field MP2RAGE acquisition and T1 mapping in healthy volunteers. The MP2RAGE optimization was performed to maximize the contrast-to-noise ratio (CNR) of T1 values in white matter (WM) and gray matter (GM) brain tissues at 0.35T. Low-field MP2RAGE images were acquired on a 0.35T MR-Linac (ViewRay MRIdian) using a multi-channel head coil. Validation of T1 mapping was performed with a ground-truth Eurospin phantom, containing inserts of known T1 values (400-850ms), with one and two average (1A and 2A) MP2RAGE scans across four acquisition sessions, resulting in eight T1 maps. Mean (±SD) T1 relative error, T1NR, and intersession coefficient of variation (CV) were determined. Whole-brain MP2RAGE scans were acquired in 5 healthy volunteers across two sessions (A and B) and T1 maps were generated. Mean (±SD) T1 values for WM and GM were determined. Whole-brain T1 histogram analysis was performed, and reproducibility was determined with the CV between sessions. Voxel-by-voxel T1 difference maps were generated to evaluate 3D spatial variation. Low-field MP2RAGE optimization resulted in parameters: MP2RAGETR of 3250ms, inversion times (TI1/TI2) of 500/1200ms, and flip angles (α1/α2) of 7/5°. Eurospin T1 maps exhibited a mean (±SD) relative error of 3.45%±1.30%, T1NR of 20.13±5.31, and CV of 2.22%±0.67% across all inserts. Whole-brain MP2RAGE images showed high anatomical quality with clear tissue differentiation, resulting in mean (±SD) T1 values: 435.36±10.01ms for WM and 623.29±14.64ms for GM across subjects, showing excellent concordance with literature. Whole-brain T1 histograms showed high intrapatient and intersession reproducibility with characteristic intensity peaks consistent with voxel-level WM and GM T1 values. Reproducibility analysis revealed a CV of 0.46%±0.31% and 0.35%±0.18% for WM and GM, respectively. Voxel-by-voxel T1 difference maps show a normal 3D spatial distribution of noise in WM and GM. Low-field MP2RAGE proved effective in generating accurate, reliable, and reproducible T1 maps with high T1NR in phantom studies and in vivo feasibility established in healthy volunteers. While current work is focused on refining the MP2RAGE protocol to enable clinically efficient OE-MRI, this study establishes a foundation for TOLD T1 mapping for hypoxia biomarkers. This advancement holds the potential to facilitate a paradigm shift toward MR-guided biological adaptation and dose painting by leveraging 3D hypoxic spatial distributions and improving outcomes in conventionally challenging-to-treat cancers.

Associations between Earlobe Creases and Magnetic Resonance Imaging Small Vessel Disease Markers in a Chinese Cohort of Patients with Ischemic Stroke

Plain Language SummaryEarly detection of subtle white matter hyperintensities (WMHs) or brain atrophy might be important in terms of diagnosis and treatment. We hypothesize that earlobe crease (ELC), a visible sign of aging, may correlate with and aid in the early identification of WMHs and brain atrophy. We reported the association between the ELC and WMHs and brain atrophy among 730 patients with acute ischemic stroke (AIS). We observed that in AIS patients the presence of ELC, especially bilateral ELC, showed independent associations with both WMHs and brain atrophy, particularly among those younger than 68 years old. Our findings suggest that ELC, especially bilateral ELC, might be an easy-to-observe and widely used indicator for predicting the presence of WMHs or brain atrophy.

A Diffusion Tensor Imaging White Matter Atlas of the Domestic Canine Brain

Abstract There is increasing reliance on magnetic resonance imaging (MRI) techniques in both research and clinical settings. However, few standardized methods exist to permit comparative studies of brain pathology and function. To help facilitate these studies, we have created a detailed, MRI-based white matter atlas of the canine brain using diffusion tensor imaging. This technique, which relies on the movement properties of water, permits the creation of a three-dimensional diffusivity map of white matter brain regions that can be used to predict major axonal tracts. To generate an atlas of white matter tracts, thirty neurologically and clinically normal dogs underwent MRI imaging under anesthesia. High-resolution, three-dimensional T1-weighted sequences were collected and averaged to create a population average template. Diffusion weighted imaging sequences were collected and used to generate diffusivity maps, which were then registered to the T1-weighted template. Using these diffusivity maps, individual white matter tracts—including association, projection, commissural, brainstem, olfactory and cerebellar tracts—were identified with reference to previous canine brain atlas sources. To enable the use of this atlas, we created downloadable overlay files for each white matter tract identified using manual segmentation software. In addition, using diffusion tensor imaging tractography, we created tract files to delineate major projection pathways. This comprehensive white matter atlas serves as a standard reference to aid in the interpretation of quantitative changes in brain structure and function in clinical and research settings.

Using mechanistic knowledge to appraise contemporary approaches to the rehabilitation of upper limb function following stroke.

It is a paradox of neurological rehabilitation that, in an era in which preclinical models have produced significant advances in our mechanistic understanding of neural plasticity, there is inadequate support for many therapies recommended for use in clinical practice. When the goal is to estimate the probability that a specific form of therapy will have a positive clinical effect, the integration of mechanistic knowledge (concerning 'the structure or way of working of the parts in a natural system') may improve the quality of inference. This is illustrated by analysis of three contemporary approaches to the rehabilitation of lateralized dysfunction affecting people living with stroke: constraint-induced movement therapy; mental practice; and mirror therapy. Damage to 'cross-road' regions of the structural (white matter) brain connectome generates deficits that span multiple domains (motor, language, attention and verbal/spatial memory). The structural integrity of these regions determines not only the initial functional status, but also the response to therapy. As structural disconnection constrains the recovery of functional capability, 'disconnectome' modelling provides a basis for personalized prognosis and precision rehabilitation. It is now feasible to refer a lesion delineated using a standard clinical scan to a (dis)connectivity atlas derived from the brains of other stroke survivors. As the individual disconnection pattern thus obtained suggests the functional domains most likely be compromised, a therapeutic regimen can be tailored accordingly. Stroke is a complex disorder that burdens individuals with distinct constellations of brain damage. Mechanistic knowledge is indispensable when seeking to ameliorate the behavioural impairments to which such damage gives rise.

Integrated transcriptomic and proteomic analyses reveal the effects of chronic benzene exposure on the central nervous system in mice

Benzene exposure is known to cause serious damage to the human hematopoietic system. However, recent studies have found that chronic benzene exposure may also cause neurological damage, but there were few studies in this issue. The aim of this study was to investigate the mechanism of damage to the central nervous system (CNS) by chronic benzene exposure with a multi-omics analysis. We established a chronic benzene exposure model in C57BL/6J mice by gavage of benzene-corn oil suspension, identified the differentially expressed proteins (DEPs) and differentially expressed genes (DEGs) in mice brain using 4D Label-free proteomic and RNA-seq transcriptomic. We observed that the benzene exposure mice had a significant loss of body weight, reduction in complete blood counts, abnormally high MRI signals in brain white matter, as well as extensive brain edema and neural demyelination. 162 DEPs were identified by the proteome, including 98 up-regulated and 64 down-regulated proteins. KEGG pathway analysis of DEPs showed that they were mainly involved in the neuro-related signaling pathways such as metabolic pathways, pathways of neurodegeneration, chemical carcinogenesis, Alzheimer disease, and autophagy. EPHX1, GSTM1, and LIMK1 were identified as important candidate DEGs/DEPs by integrated proteomic and transcriptomic analyses. We further performed multiple validation of the above DEGs/DEPs using fluorescence quantitative PCR (qPCR), parallel reaction monitoring (PRM), immunohistochemistry, and immunoblotting to confirm the reliability of the multi-omics study. The functions of these DEGs/DEPs were further explored and analyzed, providing a theoretical basis for the mechanism of nerve damage caused by benzene exposure.

Comparative profiling of white matter development in the human and mouse brain reveals volumetric deficits and delayed myelination in Angelman syndrome.

Angelman syndrome (AS), a severe neurodevelopmental disorder resulting from the loss of the maternal UBE3A gene, is marked by changes in the brain's white matter (WM). The extent of WM abnormalities seems to correlate with the severity of clinical symptoms, but these deficits are still not well characterized or understood. This study provides the first large-scale measurement of WM volume reduction in children with AS. Furthermore, we probed the underlying neuropathology by examining the progression of myelination in an AS mouse model. We conducted magnetic resonance imaging (MRI) on children with AS (n=32) and neurotypical controls (n=99) aged 0.5-12 years. In parallel, we examined myelination in postnatal Ube3a maternal-null mice (Ube3a m-/p+; AS model), Ube3a paternal-null mice (Ube3a m+/p-), and wildtype controls (Ube3a m+/p+) using immunohistochemistry, Western blotting, and electron microscopy. Our data revealed that AS individuals exhibit significant reductions in brain volume by ~1 year of age, with WM reduced by 26% and gray matter by 21% by 6-12 years of age-approximately twice the reductions observed in the adult AS mouse model. In our AS mouse model, we saw a global delay in the onset of myelination, which normalized within days (likely corresponding to months or years in human development). This myelination delay is caused by the loss of UBE3A in neurons rather than UBE3A haploinsufficiency in oligodendrocytes. Interestingly, ultrastructural analyses did not reveal any abnormalities in myelinated or unmyelinated axons. It is difficult to extrapolate the timing and duration of the myelination delay observed in AS model mice to individuals with AS. This study reveals WM deficits as a hallmark in children with AS, demonstrating for the first time that these deficits are already apparent at 1 year of age. Parallel studies in a mouse model of AS show that these deficits may be associated with delayed onset of myelination due to the loss of neuronal (but not glial) UBE3A. These findings emphasize the potential of WM as both a therapeutic target for interventions and a valuable biomarker for tracking the progression of AS and the effectiveness of potential treatments.

Numerical modelling of multiple sclerosis: A tissue-scale model of brain lesions

Multiple Sclerosis (MS) is an autoimmune condition leading to the degeneration of brain tissue, occurring when the immune system attacks the myelin sheath surrounding axons of white brain matter thereby disrupting brain signals. This study aimed to evaluate how MS lesions alter stress distribution through grey and white brain matter with lesions (active, chronic, and inactive). A linear viscoelastic model represents the tissue-scale dynamic deformation and time dependency of brain tissue. A Prony series expansion was used to model viscous effects including stress relaxation. An elastic modulus, within the viscoelastic model, was either reduced by 11 % for active lesions, or increased by 35 % increase for inactive lesions. These material properties were then implemented to model healthy tissue, active, chronically inflamed, and inactive lesions. Finite element analysis enabled stress evaluation in response to a peak cyclic displacement of 0.5 mm (1 % strain) with the healthy model acting as a control model. Chronic lesions had the largest effect on stress induced, in terms of high (171 Pa) and low stress (108 Pa). Inactive lesions induced an increase in stress of 11 Pa with areas of low stress (105 Pa). Active lesions caused the least deviation in peak induced stress (7 Pa). In conclusion, a hierarchy in stress induced across the lesion types has been found, from highest to lowest: chronic, inactive and active, with potential implications for lesion progression. In conclusion, MS lesions within brain tissue should model lesions, avoid assuming homogeneity during degeneration, and should distinguish between active and passive lesions.

Effect of Ethanol on Brain Electrical Tissue Conductivity in Social Drinkers.

How the biophysics of electrical conductivity measures relate to brain activity is poorly understood. The sedative, ethanol, reduces metabolic activity but its impact on brain electrical conductivity is unknown. To investigate whether ethanol reduces brain electrical tissue conductivity. Prospective. Fifty-two healthy volunteers (aged 18-37 years, 22 females, 30 males). 3 T, T1-weighted, multi-shot, turbo-field echo (TFE); 3D balanced fast-field echo (bFFE). Brain gray and white matter tissue conductivity measured with phase-based magnetic resonance electrical properties tomography (MREPT) compared before and 20 minutes after ethanol consumption (0.7 g/kg body weight). Differential conductivity whole brain maps were generated for three subgroups: those with strong ( > 0.1 S/m; N = 33), weak (0.02 S/m ≤ ≤ 0.1 S/m; N = 9) conductivity decrease, and no significant response ( < 0.02 S/m, N = 10). Maps were compared in the strong response group where breath alcohol rose between scans, vs. those where it fell. Average breath alcohol levels were compared to the differential conductivity maps using linear regression. T-maps were generated (threshold P < 0.05 and P < 0.001; minimum cluster 48 mm3). Differential conductivity maps were compared with ANOVA. Whole-group analysis showed decreased conductivity that did not survive statistical thresholding. Strong responders (N = 33) showed a consistent pattern of significantly decreased conductivity ( > 0.1 S/m) in frontal/occipital and cerebellar white matter. The weak response group (N = 9) showed a similar pattern of conductivity decrease (0.02 S/m ≤ ≤ 0.1 S/m). There was no significant relationship with breath alcohol levels, alcohol use, age, ethnicity, or sex. The strong responders' regional response was different between ascending (N = 12) or descending (N = 20) alcohol during the scan. Ethanol reduces brain tissue conductivity in a participant-dependent and spatially dependent fashion. 1 TECHNICAL EFFICACY: Stage 2.

Effects of Aging, Fitness, and Cerebrovascular Status on White Matter Microstructural Health.

White matter (WM) microstructural health declines with increasing age, with evidence suggesting that improved cardiorespiratory fitness (CRF) may mitigate this decline. Specifically, higher fit older adults tend to show preserved WM microstructural integrity compared to their lower fit counterparts. However, the extent to which fitness and aging independently impact WM integrity across the adult lifespan is still an open question, as is the extent to which cerebrovascular health mediates these relationships. In a large sample (N = 125, aged 25-72), we assessed the impact of age and fitness on fractional anisotropy (FA, derived using diffusion weighted imaging, DWI) and probed the mediating role of cerebrovascular health (derived using diffuse optical tomography of the cerebral arterial pulse, pulse-DOT) in these relationships. After orthogonalizing age and fitness and computing a PCA on whole brain WM regions, we found several WM regions impacted by age that were independent from the regions impacted by fitness (hindbrain areas, including brainstem and cerebellar tracts), whereas other areas showed interactive effects of age and fitness (midline areas, including fornix and corpus callosum). Critically, cerebrovascular health mediated both relationships suggesting that vascular health plays a linking role between age, fitness, and brain health. Secondarily, we assessed potential sex differences in these relationships and found that, although females and males generally showed the same age-related FA declines, males exhibited somewhat steeper declines than females. Together, these results suggest that age and fitness impact specific WM regions and highlight the mediating role of cerebrovascular health in maintaining WM health across adulthood.

Synergistic effects of GFAP and Aβ42: Implications for white matter integrity and verbal memory across the cognitive spectrum

BackgroundPlasma glial fibrillary acidic protein (GFAP), an astrocytic biomarker, has previously been linked with Alzheimer's disease (AD) status, amyloid levels, and memory performance in older adults. The neuroanatomical pathways by which astrogliosis/astrocyte reactivity might impact cognitive outcomes remains unclear. We evaluated whether plasma GFAP and amyloid levels had a synergistic effect on fornix structure, which is critically involved in AD-associated cholinergic pathways. We also examined whether fornix structure mediates associations between GFAP and verbal memory. MethodsIn a cohort of both asymptomatic and symptomatic older adults (total n = 99), we assessed plasma GFAP, amyloid-β42 (Aβ42), other AD-related proteins, and vascular markers, and we conducted comprehensive memory testing. Tractography-based methods were used to assess fornix structure with whole brain diffusion metrics to control for diffuse alterations in brain white matter. ResultsIn individuals in the low plasma amyloid-β42 (Aβ42) group, higher plasma GFAP was associated with lower fractional anisotropy (FA; p = 0.007), higher mean diffusivity (MD; p < 0.001), higher radial diffusivity (RD; p < 0.001), and higher axial diffusivity (DA; p = 0.001) in the left fornix. These associations were independent of APOE gene status, plasma levels of total tau and neurofilament light, plasma vascular biomarkers, and whole brain diffusion metrics. In a sub-analysis of participants in the low plasma Aβ42 group (n = 33), fornix structure mediated the association between higher plasma GFAP levels and lower verbal memory performance. DiscussionHigher plasma GFAP was associated with altered fornix microstructure in the setting of greater amyloid deposition. We also expanded on our prior GFAP-verbal memory findings by demonstrating that in the low plasma Aβ42 group, left fornix integrity may be a primary white matter conduit for the negative associations between GFAP and verbal memory performance. Overall, these findings suggest that astrogliosis/astrocyte reactivity may play an early, pivotal role in AD pathogenesis, and further demonstrate that high GFAP and low Aβ42 in plasma may reflect a particularly detrimental synergistic role in forniceal-memory pathways.

KARS Mutations Impair Brain Myelination by Inducing Oligodendrocyte Deficiency: One Potential Mechanism and Improvement by Melatonin.

It is very crucial to investigate key molecules that are involved in myelination to gain an understanding of brain development and injury. We have reported for the first time that pathogenic variants p.R477H and p.P505S in KARS, which encodes lysyl-tRNA synthetase (LysRS), cause leukoencephalopathy with progressive cognitive impairment in humans. The role and action mechanisms of KARS in brain myelination during development are unknown. Here, we first generated Kars knock-in mouse models throughthe CRISPR-Cas9 system. Kars knock-in mice displayed significant cognitive deficits. These mice also showed significantly reduced myelin density and content, as well as significantly decreased myelin thickness during development. In addition, Kars mutations significantly induced oligodendrocyte differentiation arrest and reduction in the brain white matter of mice. Mechanically, oligodendrocytes' significantly imbalanced expression of differentiation regulators and increased capase-3-mediated apoptosis were observed in the brain white matter of Kars knock-in mice. Furthermore, Kars mutations significantly reduced the aminoacylation and steady-state level of mitochondrial tRNALys and decreased the protein expression of subunits of oxidative phosphorylation complexes in the brain white matter. Kars knock-in mice showed decreased activity of complex IV and significantly reduced ATP production and increased reactive oxygen species in the brain white matter. Significantly increased percentages of abnormal mitochondria and mitochondrion area were observed in the oligodendrocytes of Kars knock-in mouse brain. Finally, melatonin (a mitochondrion protectant) significantly attenuated mitochondrion and oligodendrocyte deficiency in the brain white matter of KarsR504H/P532S mice. The mice treated with melatonin also showed significantly restored myelination and cognitive function. Our study first establishes Kars knock-in mammal models of leukoencephalopathy and cognitive impairment and indicates important roles of KARS in the regulation of mitochondria, oligodendrocyte differentiation and survival, and myelination during brain development and application prospects of melatonin in KARS (or even aaRS)-related diseases.

CSF1R-Related Disorder: Prevalence of CSF1R Variants and Their Clinical Significance in the UK Population.

CSF1R-related disorder (CSF1R-RD) is a devastating neurodegenerative disorder caused by variants in the colony stimulating factor-1 receptor (CSF1R) gene. CSF1R-RD leads to a variable combination of cognitive impairment, movement disorders, upper motor neuron signs, and spasticity with associated imaging abnormalities in brain white matter. Although increasingly recognized, there is evidence that it is significantly underdiagnosed or misdiagnosed, and its true prevalence is unknown. We leveraged the large data set of the UK Biobank to determine the prevalence of CSF1R mutations in the UK population and identify clinical phenotypes associated with these variants. Pathogenic and likely pathogenic CSF1R variants were identified in UK Biobank whole-exome sequencing data (N = 470,000). Medical history, including neurologic and psychiatric disease, were determined from self-reported and hospital collected codes, and the volume of MRI white matter hyperintensities were compared between variant carriers and controls. We identified 25 individuals carrying 18 unique pathogenic variants and 107 individuals carrying 44 unique likely pathogenic variants-combined prevalence 132 (∼1 in 3,500). Pathogenic CSF1R variant carriers had increased risk of psychiatric disease (OR: 5.15, p = 0.0079), depression (OR: 10.52, p = 0.0015), and Parkinson disease (OR: 19.80, p = 0.0038). Using algorithmically defined diagnosis data, pathogenic or likely pathogenic variants (the combined group) carriers were at higher risk for both dementia (OR: 2.50, p = 0.046) and vascular dementia (OR: 4.72, p = 0.032). Damaging variants in CSF1R are more common than expected in the general population and are associated with cognitive, psychiatric, and movement disorder diagnoses, which may reflect clinical manifestation of the disease. This study suggests that CSF1R-RD is either underreported, not diagnosed because of lack of genetic screening or that there is reduced penetrance.

Association between metabolic syndrome and white matter integrity in young and mid-age post-9/11 adult Veterans.

Metabolic syndrome has been associated with reduced brain white matter integrity in older individuals. However, less is known about how metabolic syndrome might impact white matter integrity in younger populations. This study examined metabolic syndrome-related global and regional white matter integrity differences in a sample of 537 post-9/11 Veterans. Metabolic syndrome was defined as ≥3 factors of: increased waist circumference, hypertriglyceridemia, low high-density lipoprotein cholesterol, hypertension, and high fasting glucose. T1 and diffusion weighted 3T MRI scans were processed using the FreeSurfer image analysis suite and FSL Diffusion Toolbox. Atlas-based regions of interest were determined from a combination of the Johns Hopkins University atlas and a Tract-Based Spatial Statistics-based FreeSurfer WMPARC white matter skeleton atlas. Analyses revealed individuals with metabolic syndrome (n = 132) had significantly lower global fractional anisotropy than those without metabolic syndrome (n = 405), and lower high-density lipoprotein cholesterol levels was the only metabolic syndrome factor significantly related to lower global fractional anisotropy levels. Lobe-specific analyses revealed individuals with metabolic syndrome had decreased fractional anisotropy in frontal white matter regions compared with those without metabolic syndrome. These findings indicate metabolic syndrome is prevalent in this sample of younger Veterans and is related to reduced frontal white matter integrity. Early intervention for metabolic syndrome may help alleviate adverse metabolic syndrome-related brain and cognitive effects with age.

Characterizing white matter connectome abnormalities in patients with temporal lobe epilepsy using threshold-free network-based statistics.

Emerging evidence illustrates that temporal lobe epilepsy (TLE) involves network disruptions represented by hyperexcitability and other seizure-related neural plasticity. However, these associations are not well-characterized. Our study characterizes the whole brain white matter connectome abnormalities in TLE patients compared to healthy controls (HCs) from the prospective Epilepsy Connectome Project study. Furthermore, we assessed whether aberrant white matter connections are differentially related to cognitive impairment and a history of focal-to-bilateral tonic-clonic (FBTC) seizures. Multi-shell connectome MRI data were preprocessed using the DESIGNER guidelines. The IIT Destrieux gray matter atlas was used to derive the 162×162 structural connectivity matrices (SCMs) using MRTrix3. ComBat data harmonization was applied to harmonize the SCMs from pre- and post-scanner upgrade acquisitions. Threshold-free network-based statistics were used for statistical analysis of the harmonized SCMs. Cognitive impairment status and FBTC seizure status were then correlated with these findings. We employed connectome measurements from 142 subjects, including 92 patients with TLE (36 males, mean age=40.1±11.7 years) and 50 HCs (25 males, mean age=32.6±10.2 years). Our analysis revealed overall significant decreases in cross-sectional area (CSA) of the white matter tract in TLE group compared to controls, indicating decreased white matter tract integrity and connectivity abnormalities in addition to apparent differences in graph theoretic measures of connectivity and network-based statistics. Focal and generalized cognitive impaired TLE patients showcased higher trend-level abnormalities in the white matter connectome via decreased CSA than those with no cognitive impairment. Patients with a positive FBTC seizure history also showed trend-level findings of association via decreased CSA. Widespread global aberrant white matter connectome changes were observed in TLE patients and characterized by seizure history and cognitive impairment, laying a foundation for future studies to expand on and validate the novel biomarkers and further elucidate TLE's impact on brain plasticity.

Radiation-Induced Cognitive Decline: Challenges and Solutions.

Radiation therapy, a common treatment for central nervous system cancers, can negatively impact cognitive function, resulting in radiation-induced cognitive decline (RICD). RICD involves a decline in cognitive abilities such as memory and attention, likely due to damage to brain white matter, inflammation, and oxidative stress. The multifactorial nature of RICD poses challenges including different mechanisms of injury (neurogenesis, oxidative stress and neuroinflammation, dendritic structure alterations and vascular effects) and confounding factors like advanced age, and pre-existing conditions. Despite these challenges, several potential solutions exist. Neuroprotective agents like antioxidants can mitigate radiation damage, while cognitive rehabilitation techniques such as cognitive training and memory strategies improve cognitive function. Advanced imaging techniques like magnetic resonance imaging (MRI) help identify vulnerable brain areas, and proton therapy offers precise targeting of cancer cells, sparing healthy tissue. Multidisciplinary care teams are crucial for managing RICD's cognitive and psychological effects. Personalized medicine, using genetic and molecular data, can identify high-risk patients and tailor treatments accordingly. Emerging therapies, including stem cell therapy and regenerative medicine, offer hope for repairing or replacing damaged brain tissue. Addressing RICD is vital for cancer survivors, necessitating consideration of cognitive function and provision of appropriate support and resources for those experiencing cognitive decline.

ω-3 PUFA for Secondary Prevention of White Matter Lesions and Neuronal Integrity Breakdown in Older Adults

Older adults with lower intake and tissue levels of long-chain ω-3 polyunsaturated fatty acids (PUFAs) eicosapentaenoic acid (EPA; 20:5) and docosahexaenoic acid (DHA; 22:6) have more brain white matter lesions (WMLs), an association suggesting that small-vessel ischemic disease, a major contributor to the development of dementia, including Alzheimer disease, may be preventable through ω-3 treatment. To determine whether ω-3 treatment reduces WML accumulation in older adults without dementia harboring WMLs and with suboptimal ω-3 status. This quadruple-blinded, placebo-controlled, randomized clinical trial with treatment stratification by apolipoprotein E ε4 allele (APOE*E4) carrier status used linear mixed-effects models to estimate mean annual change between groups. The study was conducted at Oregon Health & Science University, a major academic medical center in the Pacific Northwest, from May 2014 to final participant visit in September 2019. Data analysis concluded in July 2022. Participants were adults without dementia aged 75 years and older with WMLs greater than or equal to 5 cm3 and plasma ω-3 PUFA less than 5.5 weight percentage of total. Three-year treatment with 1.65 g of ω-3 PUFA (975 mg of EPA and 650 mg of DHA) vs a soybean oil placebo matched for taste, smell, and appearance. The primary outcome was annual WML progression measured using magnetic resonance imaging. Secondary outcomes included diffusion tensor imaging of fractional anisotropy (DTI-FA), representing neuronal integrity breakdown. A total of 102 participants (62 women [60.8%]; mean age, 81 years [range, 75-96 years]) were equally randomized, 51 per treatment group. Although the ω-3 group had less annual WML accumulation than the placebo group, the difference was not statistically significant (1.19 cm3 [95% CI, 0.64-1.74 cm3] vs 1.34 cm3 [95% CI, 0.80-1.88 cm3]; P = .30). Similarly, the ω-3 group had less annual DTI-FA decline than the placebo group, but the difference was not statistically significant (-0.0014 mm2/s [95% CI, -0.0027 to 0.0002 mm2/s] vs -0.0027 mm2/s [95% CI, -0.0041 to -0.0014 mm2/s]; P = .07). Among APOE*E4 carriers, the annual DTI-FA decline was significantly lower in the group treated with ω-3 than the placebo group (-0.0016 mm2/s [95% CI, -0.0032 to 0.0020 mm2/s] vs -0.0047 mm2/s [95% CI, -0.0067 to -0.0025 mm2/s]; P = .04). Adverse events were similar between treatment groups. In this 3-year randomized clinical trial, ω-3 treatment was safe and well-tolerated but failed to reach significant reductions in WML accumulation or neuronal integrity breakdown among all participants, which may be attributable to sample size limitations. However, neuronal integrity breakdown was reduced by ω-3 treatment in APOE*E4 carriers, suggesting that this treatment may be beneficial for this specific group. ClinicalTrials.gov Identifier: NCT01953705.